Zopiclone, chemically named (±)-6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo -[3,4b]pyrazin-5-yl-4-methylpiperazine-1-carboxylate, is a non-benzodiazepine hypnotic which has the following structure:
Zopiclone and some of its uses are described by U.S. Pat. Nos. 3,862,149 and 4,220,646. Uses of the optically pure (+) and (−) enantiomers of the drug (i.e., (+) -zopiclone and (−)-zopiclone) are described in U.S. Pat. No. 5,786,357 and WO 93/10788, respectively.
Zopiclone reportedly binds at or near benzodiazepine sites on GABA A macromolecular receptor complexes. Goa, K. L. and Heel, R. C. Drugs, 32:48–65 (1986). These complexes are located both within the central nervous system and peripherally (e.g., in the endocrine system), and contain binding sites for benzodiazepines and GABA. Verma, A. and Snyder, S. H., Annu. Rev. Pharmacol. Toxicol. 29:307–22 (1989). GABA receptor complexes are further associated with, and interact with, membrane channels for chloride ion transport. Upon binding to a benzodiazepine site, zopiclone is believed to allosterically modulate the activity of the complex by increasing transmembrane conductance of chloride ions. This stabilizes neuronal membrane potentials and dampens excitatory input. See Meldrum, B. S., Brit. J. Clin. Pharm. 27(suppl.1): S3–S11 (1989); Goodman & Gilman's The Pharmacological Basis of Therapeutics, Hardman, J. G., et al., eds. p. 365 (9th ed., 1996).
The metabolism of zopiclone is rapid, complex, and differs among species. Gaillot, J., et al., Pharmacology 27(supp.2): 76–91 (1983). Of the more than ten metabolites of the compound that have been identified, however, only two reportedly exhibit pharmacological activity in humans: N-desmethylzopiclone and zopiclone-N-oxide. See Goa, K. L. and Heel, R. C. Drugs, 32:48–65 (1986) (“Goa”); U.S. Pat. No. 6,339,086. Other zopiclone metabolites are reportedly inactive. Goa, FIG. 3, page 59.
Although chemically unrelated to the benzodiazepines, zopiclone exhibits pharmacological activity similar to benzodiazepines. Goa. For example, zopiclone and its optically pure enantiomers are reportedly useful in the treatment of diseases and conditions including, but not limited to, epilepsy, anxiety, aggressive behavior, muscle tension, behavioral disorders, depression, schizophrenia, and endocrine disorders. See, e.g., WO 93/10787. Racemic zopiclone has also been used to improve sleep in adults and geriatric patients with several types of sleep disorders including situational, transient primary and secondary insomnia. See, e.g., Brun, J. P., Pharm. Biochem. Behav. 29: 831–832 (1988).
Some compounds which bind to benzodiazepine sites also have an affinity for muscarinic receptors such as acetylcholine receptors. Julou, L., et al., Pharmacol. Biochem. Behav. 23:653–659 (1985). Consequently, administration of such compounds can result in adverse effects such as, but are not limited to, drymouth, thirst, slowing and acceleration of the heart, dilated pupils, blurred vision, restlessness, fatigue, headache, hallucinations and delirium. Goodman & Gilman's The Pharmacological Basis of Therapeutics, Hardman, J. G., et al., eds. p. 142 (9th ed., 1996). Many of these same adverse effects are exhibited by racemic zopiclone. Particular adverse effects exhibited by the racemic zopiclone include, but are not limited to, the development of a bitter taste due to salivary secretion of the drug, dry mouth, heart palpitations, drowsiness, morning tiredness, headache, dizziness, impairment of psychomotor skills and related effects. Compounds are therefore desired that can be used for the treatment or prevention of various disorders, but which have reduced, fewer, or different adverse effects than racemic zopiclone.